Controversial role of toll-like receptors in acute pancreatitis

Table 1 Human Toll-like receptors: Localization, known pathogen-associated molecular patterns and their producing microorganisms

	Localization	PAMP	Origin of PAMP
TLR1	Plasma membrane	Soluble factors	N. meningitidis
		Triacyl lipopeptides	Bacteria, mycobacteria
TLR2	Plasma membrane	Glycoinositolphospholipids	Trypanosoma cruzi
		Glycolipids	Treponema maltophilum
		Haemagglutinin	Virus
		Lipoarabinomannan	Mycobacteria
		Lipoprotein/lipopeptides	Various pathogens
		Lipoteichoic acid	Gram-positive bacteria
		Peptidoglycan	Gram-positive bacteria
		Phenol-soluble modulin	S. epidermidis
		Porins	Neisseria
		Zymosan	Fungi
TLR3	Endosome	Double-stranded RNA	Virus
TLR4	Plasma membrane	Envelope protein	Mouse-mammary tumour virus
		Fusion protein	Respiratory syncytial virus
		Heat-shock protein 60	Chlamydia pneumoniae
		Lipopolysaccharide	Gram-negative bacteria
		Taxol	Plants
TLR5	Plasma membrane	Flagellin	Bacteria
TLR6	Plasma membrane	Diacyl lipopeptides	Mycoplasma
		Lipoteichoic acid	Gram-positive bacteria
		Zymosan	Fungi
TLR7	Endosome	Single-stranded RNA	Virus
TLR8	Endosome	Single-stranded RNA	Virus
TLR9	Endosome	DNA (CpG)	Bacteria, virus
		Haemozoin	Plasmodium spp.
			Rhodnius spp.
			Schistosoma spp.
TLR10	Endosome	Not determined	Not determined

Modified after Akira et al[7]. TLR: Toll-like receptor; PAMP: Pathogen-associated molecular patterns.

Table 2 Human toll-like receptors and a selection of known alarmins

	Proteins, peptides	Fatty acids, lipoproteins	Proteoglycans, glycosaminoglycans
TLR1	β-defensin-3
TLR2	Antiphospholipid antibodies β-defensin-3	Serum amyloid A	Biglycan
	Eosinophil-derived neurotoxin		Hyaluronic acid fragments
	Heat-shock protein 60, 70, Gp96		Versiglycan
	High-mobility group protein B1 (HMGB1)
	HMGB1-nucleosome complexes
	Surfactant protein A, D
TLR4	Antiphospholipid antibodies	Oxidised low-density protein	Biglycan
	β-defensin-2	Saturated fatty acids	Heparan sulphate fragment
	Fibrinogen	Serum amyloid A	Hyaluronic acid fragment
	Fibronectin (extra domain-A)
	High-mobility group protein B1
	Heat-shock protein 60, 70, 72, 22, Gp96
	Lactoferrin MRP8, MRP14
	Neutrophil elastase
	Surfactant protein A, D
	Tenascin-C (fibrinogen-like globe)

Modified after Paccinini et al[5]. TLR: Toll-like receptor.

Table 3 Complications of severe acute pancreatitis

Pancreatic	Systemic
Abscess	Acute kidney failure
Fat necrosis	Acute liver failure
Hemorrhages	Adult respiratory distress syndrome
Infected necrosis	Disseminated intravascular coagulation
Pseudocyst formation	Encephalopathy
Sterile necrosis	Gut ischemia
	Hypocalcemia
	Paralytic ileus
	Shock

Modified after Baddeley et al[24].

Table 4 A selection of genes regulated by nuclear factor κB

Acute phase proteins	C-reactive protein
	Complement factor Bf
	Complement factor C3
	TNFβ
Adhesion molecules	E-selectin
	Intracellular cell adhesion molecule 1
	Vascular cell adhesion molecule 1
Chemokines	IL8
	Monocyte chemoattractant protein-1
	Chemokine C-C motif ligand 5 (also known as RANTES)
Cytokines	IL2, 6, 12
	ILβ
	IL1β
	TNFβ
	TNFα
Growth factors	Granulocyte colony stimulating factor
	Granulocyte-macrophage colony stimulating factor
	Macrophage colony stimulating factor

Modified after Christman et al[11]. TLR: Toll-like receptor; TNF: Tumour necrosis factor; IL: Interleukin.

Table 5 Toll-like receptors and acute pancreatitis

	Observed change	Tissue/cell	Ref.
TLR2	Increased mRNA expression	Pancreas	[35]
		Lungs	[40]
		Liver	[48,49]
	Increased protein levels	Pancreas	[35]
		Liver	[48]
	Decreased mRNA expression	Pulmonary macrophages	[43]
TLR4	Increased mRNA expression	Pancreas	[35,64,73,92]
		Lungs	[40,88]
		Liver	[48,94,96]
		Kidney	[96]
	Increased protein levels	Small intestine	[96]
		Pancreas	[35,92]
		Lungs	[88]
		Liver	[48,49]
		Intestine	[65]
		Blood monocytes	[106]
	Decreased mRNA expression	Pulmonary macrophages	[43]
TLR9	Increased mRNA expression	Pancreas	[117,118]
	Increased protein levels	Pancreas	[118]

TLR: Toll-like receptor.

Table 6 Toll-like receptor intervention in acute pancreatitis

	Substance	Ref.
TLR2	Chloroquine	[40,49]
	L-Arg	[40,49]
	WY14643	[35]
TLR4	Anti-MIF antibody	[88]
	Baicalin	[107]
	Chloroquine	[40,49]
	Emodin	[107]
	Eritoran	[83]
	L-Arg	[40,49]
	Salvia miltiorrhizae	[108,109]
TLR9	IRS954	[118]

TLR: Toll-like receptor; MIF: Migration inhibitory protein.